Abnormal glycine metabolism is observed in two clinical syndromes referred to as ketotic hyperglycinemia and nonketotic hyperglycinemia. In the latter, a deficiency of glycine synthase has been documented as the cause of the aberrant glycine metabolism. Ketotic hyperglycinemia results from an inherited deficiency of any one of five enzymes involved in the metabolism of branched-chain amino acids. Our group has provided evidence that the abnormal glycine metabolism observed in ketotic hyperglycinemia is a result of an inhibition of glycine synthase (GS) by branched-chain alpha-keto acide. A novel mechanism for this inhibition has been proposed and involves the transfer of electrons derived from the oxidation of the alpha-ketoacids to glycine synthase, thereby inhibiting its ability to oxidize glycine. We propose to provide evidence for our hypothesis by further investigating the properties of the inhibitory phenomena by kinetic analysis. Additional experimental approaches will be designed to identify inhibitors of branched-chain alpha-keto acid dehydrogenase (BCKDH). We propose to ultimately show that BCKDH and GS are located adjacent to one another on the mitrochondial membrane actually share a common subunit, lipoamide dehydrogenase.